184475-71-6

Basic information

• Product Name: 4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol
• Synonyms: FAAH-IN-2; 4-(3-Chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline;4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinol;O-Desmorpholinopropyl Gefitinib;4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol;4-(3-Chlor-4-fluorophenylamino)-7-methoxyquinazolin-6-ol;Gefitinib Intermediate 1;4-(3-Chloro-4-fluoroanilino)-6-hydroxy-7-methoxyquinazoline
• CAS NO: 184475-71-6
• Molecular Formula: C₁₅H₁₁ClFN₃O₂
• Molecular Weight: 319.72
• EINECS: 1806241-263-5
• Product Categories: Gefitinib;Various Metabolites and Impurities;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals
• Mol File: 184475-71-6.mol
• Article Data: 51

Chemical Properties

• Melting Point: >260°C (dec.)
• Boiling Point: 478.809 °C at 760 mmHg
• Flash Point: 243.375 °C
• Appearance: tan solid
• Density: 1.49 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.702
• Storage Temp.: -20°C Freezer
• Solubility: DMSO (Slightly), Methanol (Very Slightly, Heated)
• PKA: 8.18±0.40(Predicted)
• CAS DataBase Reference: 4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol(CAS DataBase Reference)
• NIST Chemistry Reference: 4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol(184475-71-6)
• EPA Substance Registry System: 4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol(184475-71-6)

Safety Data

• Hazardous Substances Data: 184475-71-6(Hazardous Substances Data)

Usage

Chemical Properties

Tan Solid

Uses

Different sources of media describe the Uses of 184475-71-6 differently. You can refer to the following data:
1. A metabolite of Gefitinib
2. A metabolite of Gefitinib.

InChI:InChI=1/C15H11ClFN3O2/c1-22-14-6-12-9(5-13(14)21)15(19-7-18-12)20-8-2-3-11(17)10(16)4-8/h2-7,21H,1H3,(H,18,19,20)

Synthetic route

4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl acetate (788136-89-0) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
With ammonium hydroxide In methanol at 20℃; for 13h; Inert atmosphere;	99%
With sodium methylate In methanol for 3h; Reflux;	95.3%
With methanol; ammonium hydroxide at 20℃; for 3h;	95%

3-chloro-4-fluorophenylamine (367-21-5) + 2-amino-5-hydroxy-4-methoxybenzonitrile + N,N-dimethyl-formamide dimethyl acetal (4637-24-5) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
With acetic acid In toluene at 65℃; for 7h; Solvent; Temperature; Concentration; Reagent/catalyst; Inert atmosphere;	97%

4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl acetate hydrochloride → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Stage #1: 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl acetate hydrochloride With lithium hydroxide; water In methanol at 20℃; for 0.5h; Stage #2: With acetic acid In methanol; water	94%
With lithium hydroxide; water In methanol at 20℃; for 0.5h;	94%
Stage #1: 4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl acetate hydrochloride With methanol; lithium hydroxide; water at 20℃; for 0.5h; Stage #2: With acetic acid In water	94%

6-(benzyloxy)-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine (913819-12-2) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
With methanesulfonic acid In chloroform for 5h; Reflux;	91%
With trifluoroacetic acid at 75℃; for 4h;	90%
With palladium 10% on activated carbon; hydrogen In methanol under 3102.97 Torr; for 24h;	82%

N,N'-bis(3-chloro-4-fluorophenyl)formamidine (727658-04-0) + 2-amino-5-hydroxy-4-methoxybenzonitrile → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
With toluene-4-sulfonic acid In toluene at 110℃; for 5h;	84.2%

4-chloro-7-methoxyquinazolin-6-yl acetate hydrochloride salt + 3-chloro-4-fluorophenylamine (367-21-5) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Stage #1: 4-chloro-7-methoxyquinazolin-6-yl acetate hydrochloride salt; 3-chloro-4-fluorophenylamine In N,N-dimethyl-formamide at 80℃; for 1h; Stage #2: With ammonia; water In methanol for 2h; Reflux;	75%

C30H24ClFN3O4Pol → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
With trifluoroacetic acid In dichloromethane at 20℃; not specified;	44%

4-chloro-7-methoxyquinazolin-6-yl acetate hydrochloride salt → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: propan-2-ol / 5 h / 90 °C 2: 90 percent / ammonia / methanol; H2O / 24 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: toluene; isopropyl alcohol / 3 h / 20 - 65 °C 2: lithium hydroxide / water; methanol / 1 h / 20 °C View Scheme

6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one (179688-53-0) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 92 percent / N,N-diethylaniline; phosphoryl chloride / 1 h / 80 - 100 °C 2: propan-2-ol / 5 h / 90 °C 3: 90 percent / ammonia / methanol; H2O / 24 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: SOCl2 2: NH4OH / methanol View Scheme
Multi-step reaction with 3 steps 1: trichlorophosphate / toluene / Reflux 2: pyridine / isopropyl alcohol / Reflux 3: water; sodium hydroxide / methanol View Scheme

3H-6,7-dimethoxyquinazolin-4-one (13794-72-4) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: L-methionine; methanesulfonic acid / 12 h / Heating 2: pyridine; 4-(dimethylamino)pyridine / 6 h / 100 °C 3: 92 percent / N,N-diethylaniline; phosphoryl chloride / 1 h / 80 - 100 °C 4: propan-2-ol / 5 h / 90 °C 5: 90 percent / ammonia / methanol; H2O / 24 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: methionine; MeSO3H / 3 h / 100 °C 2: pyridine 3: SOCl2 4: NH4OH / methanol View Scheme
Multi-step reaction with 5 steps 1: methanesulfonic acid; L-methionine / 120 °C 2: pyridine; dmap / 100 °C 3: trichlorophosphate / toluene / Reflux 4: pyridine / isopropyl alcohol / Reflux 5: water; sodium hydroxide / methanol View Scheme

6-hydroxy-7-methoxyquinazolin-4(3H)-one (179688-52-9) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: pyridine; 4-(dimethylamino)pyridine / 6 h / 100 °C 2: 92 percent / N,N-diethylaniline; phosphoryl chloride / 1 h / 80 - 100 °C 3: propan-2-ol / 5 h / 90 °C 4: 90 percent / ammonia / methanol; H2O / 24 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: pyridine 2: SOCl2 3: NH4OH / methanol View Scheme
Multi-step reaction with 4 steps 1: pyridine; dmap / 100 °C 2: trichlorophosphate / toluene / Reflux 3: pyridine / isopropyl alcohol / Reflux 4: water; sodium hydroxide / methanol View Scheme

6-acetoxy-4-chloro-7-methoxyquinazoline (230955-75-6) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: NH4OH / methanol View Scheme
Multi-step reaction with 2 steps 1: pyridine / isopropyl alcohol / Reflux 2: water; sodium hydroxide / methanol View Scheme
Multi-step reaction with 2 steps 1: isopropyl alcohol / 5 h / 88 °C 2: water; sodium hydroxide / methanol / 6 h / 20 °C View Scheme

2-carboethoxy-4,5-dimethoxyaniline (20323-74-4) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 6 steps 1: 160 - 170 °C 2: methanesulfonic acid; L-methionine / 120 °C 3: pyridine; dmap / 100 °C 4: trichlorophosphate / toluene / Reflux 5: pyridine / isopropyl alcohol / Reflux 6: water; sodium hydroxide / methanol View Scheme
Multi-step reaction with 6 steps 1: 165 - 170 °C 2: L-methionine; methanesulfonic acid 3: pyridine / 100 °C 4: thionyl chloride; N,N-dimethyl-formamide / 90 °C 5: isopropyl alcohol / Reflux 6: ammonia / water; methanol / 24 h / 20 °C View Scheme

ethyl 2-nitro-4,5-dimethoxybenzoate (100905-33-7) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 7 steps 1: palladium on activated charcoal; hydrogen 2: 160 - 170 °C 3: methanesulfonic acid; L-methionine / 120 °C 4: pyridine; dmap / 100 °C 5: trichlorophosphate / toluene / Reflux 6: pyridine / isopropyl alcohol / Reflux 7: water; sodium hydroxide / methanol View Scheme
Multi-step reaction with 7 steps 1: iron; hydrogenchloride / ethanol; water / Reflux 2: 165 - 170 °C 3: L-methionine; methanesulfonic acid 4: pyridine / 100 °C 5: thionyl chloride; N,N-dimethyl-formamide / 90 °C 6: isopropyl alcohol / Reflux 7: ammonia / water; methanol / 24 h / 20 °C View Scheme

ethyl veratrate (3943-77-9) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 8 steps 1: nitric acid; acetic acid / 0 - 5 °C 2: palladium on activated charcoal; hydrogen 3: 160 - 170 °C 4: methanesulfonic acid; L-methionine / 120 °C 5: pyridine; dmap / 100 °C 6: trichlorophosphate / toluene / Reflux 7: pyridine / isopropyl alcohol / Reflux 8: water; sodium hydroxide / methanol View Scheme
Multi-step reaction with 8 steps 1: nitric acid / 0 °C 2: iron; hydrogenchloride / ethanol; water / Reflux 3: 165 - 170 °C 4: L-methionine; methanesulfonic acid 5: pyridine / 100 °C 6: thionyl chloride; N,N-dimethyl-formamide / 90 °C 7: isopropyl alcohol / Reflux 8: ammonia / water; methanol / 24 h / 20 °C View Scheme

Veratric acid (93-07-2) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 9 steps 1: sulfuric acid / Reflux 2: nitric acid; acetic acid / 0 - 5 °C 3: palladium on activated charcoal; hydrogen 4: 160 - 170 °C 5: methanesulfonic acid; L-methionine / 120 °C 6: pyridine; dmap / 100 °C 7: trichlorophosphate / toluene / Reflux 8: pyridine / isopropyl alcohol / Reflux 9: water; sodium hydroxide / methanol View Scheme
Multi-step reaction with 9 steps 1: sulfuric acid 2: nitric acid / 0 °C 3: iron; hydrogenchloride / ethanol; water / Reflux 4: 165 - 170 °C 5: L-methionine; methanesulfonic acid 6: pyridine / 100 °C 7: thionyl chloride; N,N-dimethyl-formamide / 90 °C 8: isopropyl alcohol / Reflux 9: ammonia / water; methanol / 24 h / 20 °C View Scheme

2-Amino-4,5-dimethoxybenzoic acid (5653-40-7) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: trimethyl orthoformate / methanol / 4 h / 70 °C / Reflux 2.1: methanesulfonic acid; DL-methionine / 3 h / 130 °C / Cooling with ice 2.2: pH 7 3.1: pyridine / 3 h / 20 - 100 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 3 h / 70 °C 5.1: isopropyl alcohol / 5 h / 88 °C 6.1: water; sodium hydroxide / methanol / 6 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1: trimethyl orthoformate / methanol / 4 h / 70 °C 2: DL-methionine; methanesulfonic acid / 3 h / 130 °C 3: pyridine / 3 h / 100 °C 4: thionyl chloride / N,N-dimethyl-formamide / 3 h / 70 °C 5: isopropyl alcohol / 5 h / 88 °C 6: sodium hydroxide; methanol / 6 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1: water / Microwave irradiation 2: magnesium sulfate; methanesulfonic acid 3: pyridine / 20 °C 4: triethylamine; trichlorophosphate / acetonitrile / 80 °C 5: 1,4-dioxane 6: sodium hydroxide / water; tetrahydrofuran / 4 h / 20 °C View Scheme

methyl 2-amino-4,5-dimethoxybenzoate (26759-46-6) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 6 steps 1: formamide / 2 h / 190 - 200 °C 2: methanesulfonic acid; L-methionine / 5 h / 150 - 160 °C 3: pyridine / 3 h / Heating / reflux 4: trichlorophosphate / 3 h / Heating / reflux 5: isopropyl alcohol / 3 h / Heating / reflux 6: methanol; lithium hydroxide; water / 0.5 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1: methanol; N,N-dimethyl-formamide / Inert atmosphere 2: methanesulfonic acid; DL-methionine / Inert atmosphere 3: pyridine / Inert atmosphere 4: thionyl chloride / N,N-dimethyl-formamide / Inert atmosphere 5: isopropyl alcohol / Inert atmosphere 6: ammonium hydroxide / 3 h / Inert atmosphere; Reflux View Scheme

3-chloro-4-fluorophenylamine (367-21-5) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine; trichlorophosphate / toluene / 20 - 60 °C 1.2: 2 h / 65 °C 2.1: lithium hydroxide; water / methanol / 0.5 h / 20 °C View Scheme

6-(benzyloxy)-4-chloro-7-methoxyquinazoline (286371-65-1) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 2 h / 60 - 65 °C 2: methanesulfonic acid / chloroform / 5 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: isopropyl alcohol / Reflux 2: trifluoroacetic acid / 1 h / Reflux View Scheme

isovanillin (621-59-0) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 9 steps 1.1: aminosulfonic acid; sodium chlorite / water / 2 h / 5 - 8 °C 2.1: hydrogenchloride / 4 h / 50 - 55 °C 3.1: potassium carbonate; potassium iodide / acetone / 25 - 30 °C 3.2: Reflux 4.1: nitric acid; acetic acid / 14 h / 25 - 35 °C 5.1: acetic acid; iron / 50 - 60 °C 6.1: ethyl acetate / 12 h / Reflux 7.1: oxalyl dichloride; N-ethyl-N,N-diisopropylamine / chloroform / 12 h / 60 - 65 °C 8.1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 2 h / 60 - 65 °C 9.1: methanesulfonic acid / chloroform / 5 h / Reflux View Scheme
Multi-step reaction with 7 steps 1: sodium formate; formic acid; hydroxyammonium sulfate / 85 °C 2: potassium carbonate / acetonitrile / 1.5 h / Reflux 3: acetic acid; nitric acid / 1 h / Cooling with ice 4: tin(ll) chloride; hydrogenchloride / water; acetic acid / 1 h / 60 °C 5: acetic acid / benzene / 2 h / 105 °C / Dean-Stark 6: acetic acid / 3 h / 130 - 140 °C 7: palladium 10% on activated carbon; hydrogen / methanol / 24 h / 3102.97 Torr View Scheme

Isovanillic acid (645-08-9) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: hydrogenchloride / 4 h / 50 - 55 °C 2.1: potassium carbonate; potassium iodide / acetone / 25 - 30 °C 2.2: Reflux 3.1: nitric acid; acetic acid / 14 h / 25 - 35 °C 4.1: acetic acid; iron / 50 - 60 °C 5.1: ethyl acetate / 12 h / Reflux 6.1: oxalyl dichloride; N-ethyl-N,N-diisopropylamine / chloroform / 12 h / 60 - 65 °C 7.1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 2 h / 60 - 65 °C 8.1: methanesulfonic acid / chloroform / 5 h / Reflux View Scheme
Multi-step reaction with 8 steps 1: sulfuric acid / methanol / Reflux 2: potassium carbonate / butanone / Reflux 3: nitric acid; acetic acid / 30 °C 4: iron; ammonium chloride / methanol; water / Reflux 5: acetic acid; formamide / Reflux 6: trichlorophosphate; N,N-dimethyl-formamide / Reflux 7: isopropyl alcohol / Reflux 8: trifluoroacetic acid / 1 h / Reflux View Scheme

3-hydroxy-4-methoxybenzoate (6702-50-7) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: potassium carbonate; potassium iodide / acetone / 25 - 30 °C 1.2: Reflux 2.1: nitric acid; acetic acid / 14 h / 25 - 35 °C 3.1: acetic acid; iron / 50 - 60 °C 4.1: ethyl acetate / 12 h / Reflux 5.1: oxalyl dichloride; N-ethyl-N,N-diisopropylamine / chloroform / 12 h / 60 - 65 °C 6.1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 2 h / 60 - 65 °C 7.1: methanesulfonic acid / chloroform / 5 h / Reflux View Scheme
Multi-step reaction with 7 steps 1: potassium carbonate / butanone / Reflux 2: nitric acid; acetic acid / 30 °C 3: iron; ammonium chloride / methanol; water / Reflux 4: acetic acid; formamide / Reflux 5: trichlorophosphate; N,N-dimethyl-formamide / Reflux 6: isopropyl alcohol / Reflux 7: trifluoroacetic acid / 1 h / Reflux View Scheme

methyl 3-(benzyloxy)-4-methoxy-benzoate (57535-57-6) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 6 steps 1: nitric acid; acetic acid / 14 h / 25 - 35 °C 2: acetic acid; iron / 50 - 60 °C 3: ethyl acetate / 12 h / Reflux 4: oxalyl dichloride; N-ethyl-N,N-diisopropylamine / chloroform / 12 h / 60 - 65 °C 5: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 2 h / 60 - 65 °C 6: methanesulfonic acid / chloroform / 5 h / Reflux View Scheme
Multi-step reaction with 6 steps 1: nitric acid; acetic acid / 30 °C 2: iron; ammonium chloride / methanol; water / Reflux 3: acetic acid; formamide / Reflux 4: trichlorophosphate; N,N-dimethyl-formamide / Reflux 5: isopropyl alcohol / Reflux 6: trifluoroacetic acid / 1 h / Reflux View Scheme

methyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate (164161-49-3) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: acetic acid; iron / 50 - 60 °C 2: ethyl acetate / 12 h / Reflux 3: oxalyl dichloride; N-ethyl-N,N-diisopropylamine / chloroform / 12 h / 60 - 65 °C 4: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 2 h / 60 - 65 °C 5: methanesulfonic acid / chloroform / 5 h / Reflux View Scheme
Multi-step reaction with 5 steps 1: iron; ammonium chloride / methanol; water / Reflux 2: acetic acid; formamide / Reflux 3: trichlorophosphate; N,N-dimethyl-formamide / Reflux 4: isopropyl alcohol / Reflux 5: trifluoroacetic acid / 1 h / Reflux View Scheme

methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate (855793-63-4) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: ethyl acetate / 12 h / Reflux 2: oxalyl dichloride; N-ethyl-N,N-diisopropylamine / chloroform / 12 h / 60 - 65 °C 3: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 2 h / 60 - 65 °C 4: methanesulfonic acid / chloroform / 5 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: acetic acid; formamide / Reflux 2: trichlorophosphate; N,N-dimethyl-formamide / Reflux 3: isopropyl alcohol / Reflux 4: trifluoroacetic acid / 1 h / Reflux View Scheme

6-(benzyloxy)-7-methoxyquinazolin-4(3H)-one (286371-64-0) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: oxalyl dichloride; N-ethyl-N,N-diisopropylamine / chloroform / 12 h / 60 - 65 °C 2: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 2 h / 60 - 65 °C 3: methanesulfonic acid / chloroform / 5 h / Reflux View Scheme
Multi-step reaction with 3 steps 1: trichlorophosphate; N,N-dimethyl-formamide / Reflux 2: isopropyl alcohol / Reflux 3: trifluoroacetic acid / 1 h / Reflux View Scheme

C18H19N3O2 → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid / 3 h / 130 - 140 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 24 h / 3102.97 Torr View Scheme

2-methoxy-5-cyanophenol (52805-46-6) → 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6)

Conditions	Yield
Multi-step reaction with 6 steps 1: potassium carbonate / acetonitrile / 1.5 h / Reflux 2: acetic acid; nitric acid / 1 h / Cooling with ice 3: tin(ll) chloride; hydrogenchloride / water; acetic acid / 1 h / 60 °C 4: acetic acid / benzene / 2 h / 105 °C / Dean-Stark 5: acetic acid / 3 h / 130 - 140 °C 6: palladium 10% on activated carbon; hydrogen / methanol / 24 h / 3102.97 Torr View Scheme
Multi-step reaction with 4 steps 1: potassium carbonate / methanol / 1 h / 65 °C / Inert atmosphere 2: nitric acid; acetic acid / 0 - 25 °C / Inert atmosphere 3: palladium 10% on activated carbon; hydrogen / methanol / 1.5 h / 20 °C / 1520.1 - 2280.15 Torr 4: acetic acid / toluene / 7 h / 65 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: potassium carbonate / methanol / 1 h / 65 °C / Inert atmosphere 2: nitric acid; acetic acid / 0 - 25 °C / Inert atmosphere 3: tetrabutylammomium bromide; sodium dithionite; water / methanol / 30 °C / Inert atmosphere 4: acetic acid / 110 °C / Inert atmosphere 5: trifluoroacetic acid / 4 h / 75 °C View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile / 0.17 h / 20 °C 1.2: 5 h / Reflux 2.1: acetic acid; nitric acid / 1 h / Cooling with ice 3.1: palladium 10% on activated carbon; hydrogen / methanol / 20 °C / 2327.23 Torr 4.1: toluene-4-sulfonic acid / toluene / 5 h / 110 °C View Scheme

propargyl bromide (106-96-7) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → 4-(3'-chloro-4'-fluoroanilino)-6-(prop-2-ynyloxy)-7-methoxyquinazoline (1214731-77-7)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere;	99%

tert-butyl 3-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]propanoate (217817-01-1) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → 3-(2-(2-(2-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)ethoxy)ethoxy)ethoxy)tert-butyl propionate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 1h;	98.5%

(E)-methyl 3-(4-(2-(tosyloxy)ethoxy)phenyl)acrylate (1012057-56-5) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → (E)-methyl 3-(4-(2-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)ethoxy)phenyl) acrylate (1012057-57-6)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h;	98%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h;	98%
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 24h;	98%

trifluoroacetic acid (76-05-1) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) + tert-butyl 4-(3-bromopropyl)-piperazine-1-carboxylate (655225-02-8) → C27H33ClFN5O4*C2HF3O2

Conditions	Yield
Stage #1: 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline; tert-butyl 4-(3-bromopropyl)-piperazine-1-carboxylate With potassium carbonate In N,N-dimethyl-formamide at 80℃; Stage #2: trifluoroacetic acid In methanol; water	97%

trifluoromethylsulfonic anhydride (358-23-6) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → 4-(3'-chloro-4'-fluorophenylamino)-7-methoxy-6-(trifluoromethanesulfonyloxy)quinazoline (451494-86-3)

Conditions	Yield
With pyridine at 0 - 20℃; Inert atmosphere;	94%
With pyridine at -6 - 20℃;	62%

N-phthaloylglycine chloride (6780-38-7) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → C25H16ClFN4O5

Conditions	Yield
With dmap In dichloromethane at 20℃; for 4.5h; Inert atmosphere; Cooling with ice;	93.2%

1-bromo-6-hexanol (4286-55-9) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → 6-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)hexan-1-ol (1012057-92-9)

Conditions	Yield
Stage #1: 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 0.166667h; Stage #2: 1-bromo-6-hexanol In N,N-dimethyl-formamide at 60℃; for 6h;	93%

methanesulfonic acid 2-[2-(2-{2-[3-(2,2,2-trifluoro-1,1-bis-trifluoromethyl-ethoxy)-2,2-bis-(2,2,2-trifluoro-1,1-bis-trifluoromethyl-ethoxymethyl)-propoxy]-ethoxy}-ethoxy)-ethoxy]-ethyl ester (939056-49-2) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → N-(3-chloro-4-fluorophenyl)-7-methoxy-6-((18,18,18-trifluoro-14,14-bis(((1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl)oxy)methyl)-17,17-bis(trifluoromethyl)-3,6,9,12,16-pentaoxaoctadecyl)oxy)quinazolin-4-amine

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 12h;	93%

10-(3-chloropropyl)-1,4,7,10-tetraazacyclododecan-1,4,7-tricarboxylic acid tri-tert-butyl ester + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → 10-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)-1,4,7,10-tetraazacyclododecan-1,4,7-tricarboxylic acid tri-tert-butyl ester

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 130℃; for 6h;	92.8%
With potassium carbonate In N,N-dimethyl-formamide at 130℃; for 6h;	66%

4-(3-chloropropyl)morpholine (7357-67-7) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → gefitinib (184475-35-2)

Conditions	Yield
With 18-crown-6 ether; potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 60℃; for 3h; Reagent/catalyst; Temperature;	92%
With tetrabutylammomium bromide; sodium carbonate; potassium iodide In iso-butanol Reflux;	90%
In N,N-dimethyl-formamide at 80 - 90℃; Concentration;	88%

1-chloro-3-hydroxypropane (627-30-5) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → M 527301 (1221965-74-7)

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile for 12h; Reflux;	91%

7-(3-chloropropyl)-1,4,7-triazacyclononan-1,4-dicarboxylic acid di-tert-butyl ester + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → 7-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)-1,4,7-triazacyclononan-1,4-dicarboxylic acid di-tert-butyl ester

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 130℃; for 6h;	89.8%
With potassium carbonate In N,N-dimethyl-formamide at 130℃; for 6h;	66%

3-morpholinopropyl 4-methylbenzenesulfonate (957621-67-9) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → gefitinib (184475-35-2)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 6h; Solvent; Temperature;	89.5%

methanesulfonic acid 3-morpholin-4-yl-propyl ester (1018895-28-7) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → gefitinib (184475-35-2)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 6h; Solvent; Temperature;	89.2%

1,3-chlorobromopropane (109-70-6) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → 6-(3-chloropropoxy)-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-ylamine (912556-91-3)

Conditions	Yield
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 40℃; for 6h;	89%
With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 40℃; for 6h;	89%
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 4h;
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 4h; Heating;	Ca. 330 mg

ethyl 5-bromovalerate (14660-52-7) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → ethyl 4-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)pentanoate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 0.5h;	88%

4-(3-chloropropyl)morpholine (7357-67-7) + ethylene glycol (107-21-1) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → gefitinib ethylene glycol

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 70 - 80℃; for 8h;	85.9%

allyl bromide (106-95-6) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → (6-allyloxy-7-methoxy-quinazolin-4-yl)-(3-chloro-4-fluoro-phenyl)-amine

Conditions	Yield
With potassium carbonate In acetone at 90℃; for 4h;	82%

4-bromoethylbutanoate (2969-81-5) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → ethyl 4-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)butanoate (1012057-14-5)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 0.5h;	81%

ethyl 17-[[(4-methylbenzene)sulfonyl]oxy]-3,6,9,12,15-pentaoxaheptadecanoate + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → ethyl 1-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl]-1,4,7,10,13,16-hexaoxaoctadecan-18-oate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; Inert atmosphere;	80%

4-benzyl-6-(3-chloropropyl)octahydropyrrolo[3,4-b][1,4]oxazine + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → 6-(3-(4-benzylhexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)propoxy)-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine (1438075-59-2)

Conditions	Yield
With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 90℃; for 18h;	79.59%
With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 90℃; for 18h;	79.59%

2-bromoethyl 2,3,4-tri-O-acetyl-β-D-xylopyranoside (86651-36-7) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → 2-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)ethyl 2,3,4-tri-O-acetyl-β-D-xylopyranoside

Conditions	Yield
Stage #1: 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: 2-bromoethyl 2,3,4-tri-O-acetyl-β-D-xylopyranoside In N,N-dimethyl-formamide at 80℃; for 8h; Inert atmosphere;	79%

4 (3-bromopropyl)-morpholine (125422-83-5) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → gefitinib (184475-35-2)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 12h;	78%

2-(3-chloropropyl)octahydrocyclopenta[c]pyrrole (1438081-50-5) + 4-(3-chloro-4-fluorophenylamino)-6-hydroxy-7-methoxyquinazoline (184475-71-6) → N-(3-chloro-4-fluorophenyl)-6-(3-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)propoxy)-7-methoxyquinazolin-4-amine (1438073-01-8)

Conditions	Yield
With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 90℃; for 12h;	75.59%
With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 90℃; for 12h; Inert atmosphere;

Upstream product

• 286371-64-0 6-(benzyloxy)-7-methoxyquinazolin-4(3H)-one 
• 855793-63-4 methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate 
• 164161-49-3 methyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate 
• 57535-57-6 methyl 3-(benzyloxy)-4-methoxy-benzoate 
• 6702-50-7 3-hydroxy-4-methoxybenzoate 
• 645-08-9 Isovanillic acid 
• 621-59-0 isovanillin 
• 286371-65-1 6-(benzyloxy)-4-chloro-7-methoxyquinazoline 
• 367-21-5 3-chloro-4-fluorophenylamine 
• 26759-46-6 methyl 2-amino-4,5-dimethoxybenzoate 
• 5653-40-7 2-Amino-4,5-dimethoxybenzoic acid 
• 93-07-2 Veratric acid 
• 3943-77-9 ethyl veratrate 
• 100905-33-7 ethyl 2-nitro-4,5-dimethoxybenzoate 

Downstream Products

• 451494-86-3 4-(3'-chloro-4'-fluorophenylamino)-7-methoxy-6-(trifluoromethanesulfonyloxy)quinazoline 
• 1012057-14-5 ethyl 4-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)butanoate 
• 1012057-15-6 ethyl 6-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)hexanoate 
• 1012057-16-7 ethyl 7-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)heptanoate 
• 1165931-21-4 2-butyl-4-chloro-1-{3-[4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy]propyl}-1H-imidazole-5-carboxaldehyde 
• 1165931-03-2 6-[3-(benzoxazol-2-ylthio)propoxy]-N-(3-chloro-4-fluorophenyl)-7-methoxy-quinazolin-4-amine 
• 1165930-87-9 6-[3-(benzothiazol-2-ylthio)propoxy]-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine 
• 1389355-13-8 C₁₇H₁₄ClF₂N₃O₂ 
• 1389355-28-5 N-(3-chloro-4-fluorophenyl)-6-(2-[18F]fluoroethoxy)-7-methoxyquinazolin-4-amine 
• 1450754-57-0 6-(2-(3-(but-3-ynyl)-3H-diazirin-3-yl)ethoxy)-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine 
• 1428015-62-6 6-(2-aminoethoxy)-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine 
• 1221965-74-7 M 527301 

Relevant articles and documents

Method suitable for industrial production and preparation of gefitinib

The invention discloses a method suitable for industrial production and preparation of gefitinib, which takes 6, 7-dimethoxy-3H-quinazoline-4-one as a raw material, and gefitinib is obtained through four steps of chlorination, amination, demethylation and reaction with N-(3-chloropropyl) morpholine, so as to solve the problems that the existing synthetic route is complex and long, the total yield is low, a large number of environment-unfriendly reagents are used, and the technology cannot be amplified. According to the method, pyridine hydrochloride/DMSO is utilized to remove 6-position methyl in a high-selectivity manner, a key intermediate N-(3-chloro-4-fluorophenyl)-6-hydroxy-7-methoxyquinazoline-4-amine is obtained in a high yield manner, and convenient synthesis of the intermediate is realized. The synthesis method has the advantages of cheap and easily available raw materials and short route, and gefitinib and derivatives modified by different 6-site groups can be rapidly obtained. The preparation method solves the bottleneck problem of large-scale production of the active pharmaceutical ingredient gefitinib.

QUINAZOLINE DERIVATIVE AND USE THEREOF

The present invention relates to a series of quinazoline compounds, especially compounds as represented by formula (I), isomers thereof or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and use thereof as Pan-HER tyrosine kinase inhibitors.

A preparation method of gefitinib (by machine translation)

The present invention relates to organic chemical and medical technology field, in particular relates to a preparation method of gefitinib. The present invention provides a preparation method of gefitinib, obtained by formula I compounds, the formula I compound preparation method comprises the following steps: nitration reaction, oxidation reaction, selective demethylation reaction, reduction reaction, a cyclization reaction, phenolic hydroxyl acetylation reaction. The present invention provides a preparation method can at the same time reducing the cost, it is easy for the refined purification, easy preparation and control of related impurities, the overall preparation process routes are greatly optimized, is suitable for industrial scale production. (by machine translation)